Search Results (182)

Background: Pulmonary fibrosis (PF) is a progressive lung disease with limited therapies. Oral Pirfenidone (PFD), an approved anti-fibrotic, shows poor lung bioavailability and significant toxicity. S-Allylmercapto-N-acetylcysteine (ASSNAC) has been demonstrated to possess significant anti-inflammatory and antioxidant properties. Methods: In this study, dry powder inhaler formulations (DPIs) co-encapsulating ASSNAC and PFD in liposomes are reported. The formulation was prepared via spray freeze-drying (SFD) using L-leucine as both a cryoprotectant and a surface morphology modifier. The interfacial enrichment of L-leucine during atomization and freezing created a hydrophobic, corrugated surface that lowered particle surface energy, prevented liquid/solid bridge formation, and reduced hygroscopicity. Results: The resulting liposomal powders exhibited optimal aerosol performance: fine particle fraction (FPF) of 61.08% ± 2.45% and mass median aerodynamic diameter (MMAD) of 2.22 ± 0.11 µm. Cellular studies demonstrated that dual-loaded liposomes were efficiently taken up by Beas-2B and HFL-1 cells, with no cytotoxicity (cell viability > 90%) and negligible hemolysis. In the TGF-β1-induced in vitro fibrosis model, the combined treatment exerted prominent therapeutic effects. This regimen preserved normal epithelial morphology, accelerated wound repair, suppressed fibroblast invasiveness, and lowered the expression levels of Collagen I, Collagen III, and α-SMA. In bleomycin-induced pulmonary fibrosis rats, inhaled ASSNAC + PFD liposomal powder markedly relieved lung tissue injury and collagen accumulation. It restored redox balance and lowered pulmonary TGF-β1, hydroxyproline and collagen III levels. The formulation blocked TGF-β1 signaling and fibrotic gene expression. Conclusions: Pulmonary administration avoids oral pirfenidone-induced liver and stomach toxicity. Collectively, the ASSNAC + PFD co-encapsulated liposomal dry powder produced by SFD represents a safe and efficacious therapeutic strategy for PF. Full article

Clinical outcomes for brain cancer are often poor because the blood–brain/tumor barrier hinders effective drug delivery to malignant tissue. Glioblastoma, the most common primary brain malignancy in adults, has an average survival of approximately fourteen months. Here, we discuss novel strategies that our research group and others are developing to deliver chemotherapy to the brain via the nasal cavity. Although significant hurdles remain, intranasal delivery holds substantial promise for improving outcomes for patients with brain cancer. Intranasal delivery is noninvasive, permits repeated dosing, and has been shown to enable direct nose-to-brain transport that bypasses the blood–brain barrier. Challenges such as accurately targeting drugs to the appropriate region of the nasal cavity at therapeutically relevant doses, while maintaining reproducibility, make this cutting-edge approach a regulatory challenge. The prolonged path to clinical translation discourages many researchers from pursuing this potentially life-saving strategy. Nevertheless, preclinical studies demonstrate that intranasal delivery can achieve up to ten-fold higher concentrations of select drugs in the brain. Cancer chemotherapeutics span a wide range of molecular formats, from small molecules to 150-kilodalton antibodies. Accordingly, delivery strategies must be carefully matched to the molecular properties of each therapeutic. Here, we focus on the intranasal delivery of small molecule inhibitors using nanomaterial-based platforms, including aerosols, lipids, gold nanoparticles, gels, emulsions, fibers, and their combinations. Ultimately, we hope that intranasal delivery approaches will be translated to provide patients with better therapeutic outcomes. Full article

Background: While live-cell therapies face significant translational hurdles, cell-free secretomes derived from fetal progenitor cells offer a unique, scalable approach natively programmed for scarless tissue repair. Methods: This GLP-compliant study evaluated the therapeutic efficacy spectrum of an off-the-shelf, clinical-grade, intratracheal lyophilized FE002-Lu lung fibroblast conditioned medium (LFCM) across five controlled Wistar rat models of induced lung injury: bleomycin (5 mg/kg), asbestos (100 µg/rat), hyperoxia (100% oxygen exposure), silica (30 mg/rat), and lipopolysaccharide (LPS, 4 mg/kg). Following lung injury induction and symptom onset, symptomatic rats were randomized to receive intratracheal LFCM (low, mid, or high dose) or a vehicle control every 4 days for 28 days. Results: The intervention demonstrated an exceptional safety profile, maintaining 100% survival with no severe procedural toxicity across all cohorts. Across all study arms, LFCM effectively attenuated pulmonary inflammation, reducing pro-inflammatory markers (IL-1β, IL-6, TNF-α, and CINC-1) in bronchoalveolar lavage fluid. Concurrently, high LFCM doses consistently elevated the anti-inflammatory cytokine IL-10. Within the lung tissue, mid- and high doses significantly reduced key pro-fibrotic drivers, including TGF-β1, TIMP-1, WISP-1, and hydroxyproline. Treatments consistently decreased α-SMA expression and pro-fibrotic gene mRNA levels, mitigating pulmonary myofibroblast activation. This correlated with reduced Ashcroft scores and collagen deposition, thereby preserving lung architecture. Notably, the FE002-Lu LFCM treatment exerted a biphasic regulation of extracellular matrix turnover: it elevated Cathepsin-D and MMP-12 in the bleomycin arm to actively clear newly deposited fibrotic debris, while reducing these markers in the hyperoxia and LPS arms to prevent acute collateral degradation of the native lung matrix. In both particulate models (asbestos and silica), the LFCM mid-dose established an optimal therapeutic threshold, avoiding the localized secretome saturation and pro-fibrotic exacerbation occasionally observed at higher doses. Conclusions: Lyophilized FE002-Lu LFCM acts as a potent, pleiotropic biologic that effectively resolves acute pulmonary inflammation and arrests progressive fibrotic remodeling across multiple distinct in vivo models. By overcoming the cold-chain and delivery limitations inherent to pulmonary live-cell therapies, this stable, cell-free secretome represents a highly scalable, “off-the-shelf” candidate poised for non-invasive, aerosolized clinical translation. Full article

Background: Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction and tissue remodeling. Alamandine (ALA), a renin–angiotensin system (RAS) peptide with anti-inflammatory properties, remains poorly explored in allergic respiratory disease. Objectives: This study evaluated prophylactic (33 days) and therapeutic (21 days) subcutaneous ALA (50 µg/kg/day) administration in an ovalbumin (OVA)-induced rat asthma model. Methods: Twenty male Wistar rats were assigned to four groups: control (CO), OVA with prophylactic ALA (ALA-P; days 1–33), OVA with therapeutic ALA (ALA-T; days 12–33), and OVA-only control (OVA). Rats were sensitized (days 1–3) and challenged with aerosolized OVA (days 6–33). On day 34, ventilatory mechanics were assessed via FlexiVent, including methacholine challenge (12.5 mg/mL). Pulmonary inflammation was evaluated by eosinophil quantification; MrgD/Mas and AT1 receptor expression by immunohistochemistry and Western blot, respectively. Results: OVA animals exhibited elevated baseline airway resistance and bronchoconstriction, and eosinophil infiltration. ALA-T significantly attenuated the respiratory symptoms, restoring airway resistance and eosinophil infiltration to CO-group levels, whereas ALA-P exhibited only a partial reduction. MrgD and Mas expression were elevated in OVA, reflecting compensatory RAS activation, but normalized in both ALA-treated groups. No significant differences in AT1 expression were observed. Conclusions: ALA likely exerts bronchoprotective and anti-allergic effects in this model via MrgD/Mas modulation. The ALA–MrgD/Mas axis represents a potential therapeutic target for allergic airway diseases, particularly when conventional treatments are insufficient. Full article

Messenger RNA–lipid nanoparticles (mRNA-LNPs) have emerged as a transformative platform for nucleic acid therapeutics, yet their complex four-component lipid architecture comprising ionizable lipids, PEG–lipids, helper phospholipids, and cholesterol presents substantial analytical challenges for quality control and regulatory compliance. This review presents, for the first time, a critical evaluation of liquid chromatography–mass spectrometry (LC-MS) strategies specifically tailored to quantify all four lipid classes and their degradation products within mRNA-LNP formulations. Unlike prior general lipidomics reviews, we provide a comparative assessment of orthogonal LC modalities including reversed-phase ultra-high-performance liquid chromatography, hydrophilic-interaction liquid chromatography, ion-pairing reversed-phase LC, and high-performance liquid chromatography charged aerosol detection with explicit performance metrics (sensitivity, linearity, and run time). We further integrate emerging analytical frontiers—single-particle analysis, degradation product profiling (e.g., oxysterols and reactive electrophiles), and regulatory frameworks (ICH Q2(R1), Analytical Quality by Design)—to offer a practical guide for method selection. This review’s uniqueness lies in its systematic, application-focused comparison of LC-MS workflows addressing lipid-specific vulnerabilities, matrix effects, and stability-indicating parameters, filling a critical gap between analytical chemistry and mRNA-LNP product development. Full article

Cystic fibrosis (CF) is one of the most common rare genetic diseases. It is caused by pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 2200 variants have been identified in the CFTR gene that need detailed knowledge and functional characterization in order to develop specific therapeutic strategies. The traditional therapy for CF relied on addressing symptoms through mucolytic and antibiotic treatments, respiratory physiotherapy and aerosol therapy. However, in the last few years, the development of small new molecules targeting and restoring the underlying CFTR channel defect marked an important step in CF treatment. In addition, the implementation of patient-specific cellular models allowed the evaluation of pharmacological responses, leading to therapeutic advances in the direction of personalized treatment. The focus of this review is to describe and discuss the strategies for restoring the CFTR functional defects depending on the specific CFTR pathogenic variants. In particular, the review highlights the possible application of experimental and clinical drugs to CF treatment, which may allow improvements in patients’ quality of life and life expectancy. The in vitro testing of therapeutic drugs (theratyping) is performed nowadays through the use of several cellular models, especially those derived from patient-specific tissues. This topic is a hot point in CF research and the review also aims to provide an overview of the state of the art in theratyping. The novelty of this review is the integrated view of the most recent achievements in precision diagnostics and therapy of CF at the molecular, cellular and clinical level, which are able to change the natural history of this disease. Full article

Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence and argues that the field has moved beyond asking whether RNA can reach the lungs. The more consequential translational question is whether RNA cargo, nanocarrier, excipients, manufacturing process, inhalation device, and pulmonary target cell can be integrated into a reproducible therapeutic product. Current research demonstrates progress in disease-corrective mRNA expression, silencing of inflammatory and fibrotic pathways, mucosal vaccination, antiviral therapy, and localized cancer treatment, alongside advances in ionizable lipid nanoparticles, lipid–polymer hybrids, chitosan and polyethyleneimine (PEI) polyplexes, dendrimers, peptide carriers, biomimetic systems, and dry-powder formulations. Translational maturity, however, remains uneven. Many studies demonstrate carrier feasibility, reporter expression, or preclinical activity, whereas fewer establish device-compatible aerosolization, preservation of RNA integrity during processing, traversal of pulmonary barriers, target-cell engagement, repeat-dose tolerability, and clinically meaningful benefit. Development should therefore be target-defined, analytically gated, device-specific, and outcome-centered. Inhalable RNA nanomedicines are best understood as integrated pulmonary products whose success depends on preserving RNA function throughout manufacturing, aerosolization, post-deposition barrier navigation, intracellular delivery, and disease-relevant pharmacodynamic activity. Full article

Pulmonary drug delivery has become a vital route for both local and systemic treatments because of the unique structure and function of the respiratory system. Unlike oral and injectable dosage forms, inhalation offers a non-invasive, direct route to deliver medicines to the lungs, bypassing gastric degradation and first-pass hepatic metabolism. Common forms such as aerosols, solutions, suspensions, and dry powders are frequently used to treat respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). However, their effectiveness is often limited by physiological and biopharmaceutical barriers, such as mucociliary clearance, enzymatic degradation, and nonspecific deposition, which reduce drug retention and bioavailability. These issues are especially critical for poorly soluble or sensitive molecules, leading to lower drug concentrations at the target site and necessitating frequent dosing. To address these challenges, advanced nanoparticle-based delivery systems are being developed to improve drug stability, targeting, and controlled release within the lungs. At the same time, computational methods, including deposition modeling, physiologically based pharmacokinetic (PBPK) simulations, and AI-driven optimization, are increasingly used in formulation development to predict in vivo performance and boost translational success. This review covers the physiological and biological barriers to pulmonary drug delivery, explores major inhalation routes and dosage forms, and discusses new therapeutic strategies and nanoparticle platforms. It also highlights the growing role of in silico modeling and AI in accelerating the design and optimization of pulmonary treatments, while addressing current challenges, limitations, and regulatory issues in translating pulmonary nanomedicine into clinical practice. Full article

Background/Objectives: Dry powder inhalation (DPI) is a promising strategy for the treatment of respiratory diseases such as cystic fibrosis (CF), where thick and viscous mucus limits drug penetration and contributes to persistent infection and inflammation. Although inhalation allows rapid drug action with reduced systemic exposure, its efficacy depends on the ability of inhaled drugs to achieve and maintain therapeutic concentrations in the lungs and to overcome airway barriers. This study aimed to develop and characterize effervescent dry powder formulations designed to enhance mucus permeabilization through mechanical disruption while delivering an antibiotic. Methods: Effervescent microparticles containing sodium bicarbonate, an organic acid (citric or tartaric acid), and levofloxacin were produced by spray drying using a triple-fluid nozzle to control component distribution and prevent premature effervescence. The influence of functional excipients, including L-leucine and mannitol, on particle formation, aerosol performance, and process yield was evaluated. Microparticles were characterized in terms of morphology, fine particle fraction (FPF), and effervescence-related properties. Results: Formulations containing L-leucine and citric acid reduced particle agglomeration and achieved a fine particle fraction of up to approximately 18%, although with a lower process yield. In contrast, formulations based on tartaric acid and mannitol improved both production yield and aerosol performance, with FPF values increasing up to 27.3% and more efficient CO₂ release. The resulting microparticles exhibited spherical, hollow, and partially fragmented morphology, consistent with premature CO₂ generation during spray drying. Conclusions: The effervescent approach, combined with controlled spray drying parameters, represents a promising formulation strategy to modulate particle behavior and drug release in mucus-relevant environments. These findings support further investigation of effervescent DPI systems for improved pulmonary drug delivery in CF. Full article

Respiratory mucosal vaccination can induce robust humoral and cellular immune responses, as well as effective mucosal immunity at the primary site of pathogen entry, and has been shown to provide superior protection against respiratory viral infections compared with traditional approaches. Among current vaccine technologies, mRNA vaccines offer unique advantages, including rapid development, flexible antigen design, and potent immunogenicity. However, efficient mucosal delivery of mRNA remains challenging due to biological barriers within the respiratory tract, including mucus clearance, limited cellular uptake, and instability during aerosolization. Furthermore, mRNA formulations intended for respiratory mucosal delivery require more stringent safety and tolerability profiles. Recent advances in nanoparticle engineering have accelerated the development of mRNA delivery systems optimized for respiratory mucosal immunization. This review aims to evaluate how nanoparticle engineering strategies can overcome respiratory mucosal barriers and improve the safety, stability, delivery efficiency, extrahepatic expression, and immunogenicity of mRNA vaccines and therapeutics. We summarize recent progress in engineered mRNA nanoparticle platforms for respiratory mucosal immunity, encompassing modified lipid nanoparticles (LNPs), polymer-based mRNA nanoparticles, and hybrid nanoparticle systems, including lipid-inorganic, polymeric hybrid, and lipid-extracellular vesicle (EV) nanoparticles. We further discuss optimization strategies for mucosal mRNA delivery, including the incorporation of appropriate adjuvants, the development of polyethylene glycol (PEG) alternatives, and advanced delivery approaches. Finally, we highlight current challenges and future directions for the rational design of next-generation mRNA nanoparticle platforms that can induce durable and broadly protective mucosal immunity against respiratory viral infections. Full article

Background: Platinum-resistant ovarian cancer with peritoneal metastases remains a therapeutic frontier marked by limited systemic efficacy and a persistent unmet clinical need for effective locoregional strategies. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a novel minimally invasive platform designed to enhance intraperitoneal drug distribution and overcome biological barriers to chemotherapy delivery. Methods: We performed a PRISMA-compliant systematic review and meta-analysis evaluating clinical outcomes of PIPAC in platinum-resistant ovarian cancer. Primary endpoints included histologic regression (PRGS ≤ 2), severe toxicity, and 12-month overall survival, complemented by exploratory analyses of treatment feasibility, disease burden dynamics, and bidirectional therapy strategies. Results: PIPAC demonstrated a consistent signal of biologic activity, with pooled histologic response rates indicating meaningful tumor regression despite advanced disease. Severe toxicity remained low across studies, supporting the favorable tolerability of repeated intraperitoneal treatment. Survival outcomes were clinically relevant for a heavily pretreated population, while feasibility analyses suggested that PIPAC may facilitate downstream surgical opportunities in selected patients. Exploratory findings further supported the concept of intraperitoneal disease modulation, reflected by reductions in peritoneal cancer index and integration within multimodal treatment pathways. Conclusions: Beyond a purely palliative intervention, PIPAC may represent a biologically active component of personalized treatment strategies for platinum-resistant ovarian cancer. These findings redefine the therapeutic narrative from symptom control toward disease modulation and treatment escalation, underscoring the need for prospective trials to refine patient selection and optimize multimodal sequencing. Full article

Background: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that has caused repeated epidemics across Africa and the Arabian Peninsula, posing a severe and growing threat to public health and livestock. Infection in ruminants causes high neonatal mortality and catastrophic abortion storms; human disease ranges from self-limiting febrile illness to hemorrhagic fever, encephalitis, and permanent blindness. No licensed human vaccines or specific antiviral therapeutics are available, creating an urgent unmet medical need. Methods: We systematically reviewed the peer-reviewed literature on RVFV neutralizing antibodies (NAbs), extracting and synthesizing data on antibody sources, epitope specificity, in vitro neutralizing potency, in vivo protective efficacy, and molecular mechanisms of action. Results: A growing body of work has identified potent NAbs from immunized rodents, rabbits, alpacas, non-human primates, and convalescent patients. These NAbs predominantly target the Gn and Gc envelope glycoproteins. Their mechanisms include blocking host receptor (LRP1) binding, preventing the pH-dependent conformational rearrangement of the Gn–Gc complex, and directly inhibiting viral membrane fusion. Lead candidates, such as RVFV-268 and RVFV-140, achieve sub-nanogram neutralization and confer robust protection in rodent models against lethal challenge, aerosol exposure, and vertical transmission. Bispecific antibodies and combination strategies further enhance potency and the genetic barrier to viral escape. Conclusions: Substantial progress has illuminated the epitope landscape and neutralization mechanisms of RVFV, yielding promising clinical candidates. Translational challenges remain, including viral immune escape, antibody thermostability, and the need for rigorous preclinical evaluation. Future efforts should prioritize structure-guided engineering, rational antibody combinations, and testing in clinically predictive animal models. Full article

Background: Cang-ai volatile oil (CAVO) is a traditional Chinese medicine with properties that soothe the liver and alleviate depression. CAVO is widely utilized in the field of antidepressant research and has surfaced as a possible treatment for depression. Depression is a common affective disorder and effective treatment methods are still limited. CAVO is effective in treating depression; however, the exact mechanism is still unclear. This study aimed to explore the likely mechanism by which CAVO reduces symptoms of depression in rats exposed to chronic unpredictable mild stress (CUMS). Methods: We established a CUMS model in Sprague–Dawley rats and administered CAVO via nebulization to evaluate its therapeutic effect. Behavioral and histology tests were conducted to evaluate brain tissue damage. We utilized metabolomics combined with proteomics to analyze the effects of CAVO. We then assessed molecular validation to further clarify the molecular mechanism of its activity. Results: In CUMS model rats, inhaling aerosolized CAVO reduced brain pathology and depression-like behaviors. CAVO changed serum levels of inflammatory cytokines and neurotrophic factors. Biomarkers linked to CAVO’s antidepressant effects were found via metabolomics. Functional analyses highlighted key molecular players such as TrkB, and CREB, and a close association with the antidepressant action of CAVO was confirmed. Conclusions: This study reveals that CAVO reduces depression-like behaviors in CUMS rats by regulating the NT/Trk signaling pathway. These results demonstrate CAVO’s therapeutic potential and lay the groundwork for future studies and the creation of depressive treatments. Full article

The lung represents a promising yet underexploited target for RNA therapeutics due to its large surface area and accessibility via non-invasive inhalation delivery. Despite rapid advances in RNA-based modalities, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), and CRISPR-Cas systems, efficient pulmonary delivery remains a major challenge. Multiple biological barriers, such as mucus and surfactant layers, mucociliary clearance, immune surveillance, and limited cellular uptake of negatively charged nucleic acids, significantly restrict therapeutic efficacy. In addition, aerosolization processes may introduce mechanical stress, compromising RNA integrity. Nanoparticle-based delivery systems have emerged as a central strategy to address these limitations. By protecting RNA cargo, enhancing mucus penetration, and promoting cellular internalization, engineered nanoparticles enable more effective pulmonary delivery. In this review, we adopt a barrier-centered perspective to examine the key biological obstacles to lung-targeted RNA delivery and highlight recent advances in nanoparticle-mediated strategies, with a focus on lipid nanoparticles, polymeric systems, and inorganic nanomaterials. We further discuss design principles that govern RNA stability, transport, and intracellular release and critically compare the strengths, limitations, and translational potential of each platform, including considerations of toxicity, biodegradability, and clinical readiness. Finally, we outline emerging clinical applications of RNA-loaded nanoparticles, using lung cancer as a representative disease model, and discuss remaining challenges and future directions. Continued innovation in nanoparticle engineering and delivery strategies is expected to accelerate the clinical translation of RNA therapeutics for pulmonary diseases. Full article

Background: The aim of this study was to assess in vitro nebulized drug delivery during invasive and non-invasive ventilation, comparing jet nebulizers (JN) and vibrating mesh nebulizers (VMN) across various pediatric ventilation models. Methods: Drug delivery performance was compared between a continuous output JN (Aquineb) and VMN (Aerogen Solo A-VMN). The non-invasive model simulated a spontaneously breathing 9-month-old child using an anatomically correct upper airway model and breathing simulator. The invasive model used a mechanical ventilator with heated humidifier in a pediatric breathing circuit with an endotracheal tube. Nebulizers were driven with supplemental oxygen at manufacturer-recommended rates and positioned at approved locations. Absolute inhaled dose, delivery rate and residual volume were assessed using face mask, mechanical ventilation, high-flow nasal therapy and blow-by delivery methods. Dose was quantified using spectrophotometric analysis. Results: During spontaneous breathing, A-VMN delivered almost double the dose of the evaluated JN (p < 0.001), with a significantly faster delivery rate (p < 0.001) and lower residual volume (p < 0.0001). During mechanical ventilation, A-VMN demonstrated a greater than 3-fold increase in delivered dose (p < 0.0001) and faster delivery (p < 0.0001), with reduced residual volume (p < 0.001). During high-flow nasal therapy, delivery via nasal cannula was affected by gas flow rate for both devices, with A-VMN consistently delivering greater doses. A-VMN delivered significantly greater salbutamol doses during blow-by delivery. Conclusions: VMN demonstrated significantly superior dose delivery, faster delivery rates and reduced residual volumes compared to the evaluated JN across all tested pediatric respiratory support modalities. These in vitro findings provide important performance data for evidence-based device selection and warrant clinical investigation to determine potential therapeutic benefits in pediatric populations requiring aerosol therapy during respiratory support. Full article